Preclinical efficacy of Sym004, novel anti-EGFR antibody mixture, in esophageal squamous cell carcinoma cell lines

// Shota Fukuoka 1, 5 , Takashi Kojima 1 , Yoshikatsu Koga 2 , Mayumi Yamauchi 1 , Masayuki Komatsu 3 , Rie Komatsuzaki 3 , Hiroki Sasaki 3 , Masahiro Yasunaga 2 , Yasuhiro Matsumura 2 , Toshihiko Doi 1 , Atsushi Ohtsu 4, 5 1 Division of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan 2 Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan 3 Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan 4 Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan 5 Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan Correspondence to: Takashi Kojima, email: takojima@east.ncc.go.jp Keywords: esophageal squamous cell carcinoma, epidermal growth factor receptor, Sym004 Received: June 15, 2016      Accepted: December 16, 2016      Published: December 26, 2016 ABSTRACT Epidermal growth factor receptor (EGFR) is a well-validated oncological target molecule for monoclonal antibody therapies and Sym004 is a novel anti-EGFR antibody mixture comprising two recombinant chimeric IgG1 antibodies against non-overlapping epitopes of EGFR. Because EGFR is highly expressed in the majority of esophageal squamous cell carcinomas (ESCCs), we investigated the efficacy of Sym004 in human ESCC cell lines. Forty eight ESCC cell lines were treated with three kinds of anti-EGFR antibodies (Sym004, cetuximab, and panitumumab). Genetic background was investigated by next generation sequencing. The internalization of anti-EGFR antibodies into ESCC cells and inhibition of the EGFR signaling cascade by anti-EGFR antibodies were investigated in vitro . Furthermore, growth inhibition by anti-EGFR antibody treatment was investigated in vitro and in vivo . Sym004 treatments were more effective at inducing EGFR internalization and degradation than the two other anti-EGFR antibodies. Sym004 was more sensitive significantly to cell lines with EGFR gene amplification than those without amplification ( P = 0.002). Growth inhibition of Sym004 was greater than in that of cetuximab or panitumumab in vitro and in vivo . These studies showed that Sym004 exhibited antitumor activity in some ESCC cell lines in preclinical settings and warrant a clinical evaluation in patients with ESCC. EGFR amplification is a potential biomarker of response to Sym004.